D1-receptor-related priming is attenuated by antisense-meditated 'knockdown' of fosB expression

S. J. Crocker, M. Morelli, N. Wigle, Y. Nakabeppu, G. S. Robertson

研究成果: Contribution to journalArticle査読

28 被引用数 (Scopus)

抄録

Administration of dopamine receptor agonists to rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway produce changes in the denervated striatum that enable a subsequent injection to elicit more vigorous circling. The molecular basis for this behavioural phenomenon, termed priming, is unknown. D1-receptor-related priming has been associated with a profound elevation of immediate-early gene (IEG) expression in the denervated striatum. Since immediate-early genes encode known transcriptional regulating factors, this observation has led to the suggestion that IEG induction may play a role in the gene signaling pathways which mediate priming. In the present study, we addressed the role of induction of the IEG fosB in dopamine agonist-induced priming by examining whether inhibition of the synthesis of FosB proteins (FosB and ΔFosB) by intrastriatal delivery of an antisense oligonucleotide to fosB reduced apomorphine-induced priming. Intrastriatal delivery of an antisense, but not a random, oligonucleotide to fosB 18 and 6 h before apomorphine reduced the ability of this mixed D1/D2-like receptor agonist to prime circling induced by the specific D1-like receptor agonist SKF38393. Immunohistochemical analysis revealed that only the antisense oligonucleotide blocked apomorphine-induced increases in FosB-like immunoreactivity in the denervated striatum. In contrast, apomorphine-induced increases in JunB-, NGFI-A- and Fos2-16-like immunoreactivities were unaffected by either the antisense or random oligonucleotides, indicating that the antisense oligonucleotide attenuated apomorphine-induced priming by selectively blocking the synthesis of FosB proteins. Taken together, these findings suggest that fosB induction in the denervated striatum plays a role in mediating D1-receptor-related priming. Dopamine replacement therapy for Parkinson's disease is often complicated by the development of dyskinetic side effects. Results from the present study suggest that D1-receptor-mediated increases in fosB expression may be involved in those intracellular events responsible for the generation of these debilitating side effects.

本文言語英語
ページ(範囲)69-77
ページ数9
ジャーナルMolecular Brain Research
53
1-2
DOI
出版ステータス出版済み - 1 1998

All Science Journal Classification (ASJC) codes

  • 分子生物学
  • 細胞および分子神経科学

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